Dr. Chang is studying protamines—short, positively-charged proteins that condense DNA into chromatin and regulate gene expression in sperm nuclei. While eukaryotic cells use histones to package genomes in a way that allows access for transcription and replication, sperm cells must package their genomes more tightly. For this, many animals deploy protamines instead of histones. Despite sharing certain functions with highly conserved histones, protamines have independently arisen in evolution multiple times and are continuing to rapidly evolution. Using Drosophila fruit fly species as a model, Dr. Chang studies how sperm chromatin regulates gene expression and reproductive fitness. Additionally, although protamine expression is typically limited to testes, their misexpression has been observed in many cancers, indicating an opportunity for therapeutic intervention.

Regulation of gene transcription is a major mechanism cells use to modify the levels of certain proteins in response to their environment. A specific class of genes called immediate-early genes (IEGs) responds rapidly to external stimuli to adjust downstream gene transcription programs before any new proteins are synthesized. Abnormal expression of IEGs has been implicated in multiple types of cancers, as well as in neurological syndromes like addiction. Despite extensive study, the regulation of IEGs remains poorly understood. Dr. Gu’s work focuses on revealing the molecular mechanisms of IEG expression in cells and establishing model systems to study the physiological and disease-related outcomes caused by misregulation of this process. Dr. Gu [National Mah Jongg League Fellow] received her PhD from MIT and her BSc from Peking University.

Genetically engineered immune cell therapies have emerged as breakthroughs in the treatment of certain blood cancers. However, these advances have been limited to the minority of cancers that express a cell surface protein on all tumor cells; this protein is absent from essential normal tissues and can be recognized and targeted by therapeutic immune cells. Dr. Jan seeks to develop synthetic biology tools to engineer immune cells to recognize the heterogeneous tumor proteins present on many advanced cancers and then activate the body's tumor clearance mechanisms. His goal is to develop cell therapy candidates for direct translation to the care of people with advanced prostate cancer.

Immune cells called macrophages can swallow bacteria and contain them in membrane-bound compartments called phagosomes. From inside the phagosome, some bacteria stimulate immune pathways in the cytosol, but it is unclear how immune signals are transmitted across the membrane from the phagosome into the cytosol. To investigate, Dr. Jastrab [Robert Black Fellow] has developed a macrophage infection model using mutants of the bacterium Staphylococcus aureus that stimulate an immune complex in the cytosol called the inflammasome. He aims to identify the host and microbial pathways that facilitate activation of the inflammasome during infection. Because the activation of cytosolic immune receptors by phagosomal bacteria may be important in protection against colorectal cancer, Dr. Jastrab’s work aims to elucidate pathways that may be manipulated to prevent tumorigenesis and enhance anti-tumor immunity. Dr. Jastrab received his MD, PhD from New York University School of Medicine, New York and his BS from Tufts University, Medford.

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Dr. Owens [Suzanne and Bob Wright Fellow] focuses on heat shock proteins (HSPs) and their “master regulator” called heat shock transcription factor 1 (HSF1). The transformation and growth of cancers causes a wide array of cellular stresses including metabolic changes, genomic instability, and protein misfolding that would halt the growth of a normal cell. Tumor cells, however, depend on cellular stress response machinery, like HSPs, for their survival. HSF1 is critical to tumor development and progression, and HSF1 activity is strongly correlated with poor prognosis in many common cancers. For decades, efforts to develop cancer therapies targeting HSPs have failed. Dr. Owens aims to understand how HSPs and HSF1 interact to regulate activity, and how this regulation is co-opted to promote tumor growth and progression.